Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nonsteroidal antiinflammatory drugs (NSAIDs) can prevent colorectal tumorigenesis in humans and in rodents. In vitro and in vivo studies indicate that one of their principal antineoplastic avenues is the induction of apoptosis. We have shown previously that NS-398, which selectively inhibits cyclooxygenase-2 (COX-2) over cyclooxygenase-1, induces apoptosis of colorectal tumour cells and elevates COX-2 protein expression. Here, we have determined that the extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway mediates these effects of NS-398. Treatment of HT29 colorectal carcinoma cells with 75 microM NS-398 caused activation of ERK-1/-2 but not of the p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases. This was apparent at 24 hr and maintained at 72 hr. U0126, a specific inhibitor of the ERK-activating kinases MEK-1/-2, prevented the activation of ERK induced by NS-398 and blocked the increase in COX-2 protein expression seen when HT29 cells were treated with NS-398 alone. The activation of ERK by NS-398 preceded and accompanied a decrease in attached cell yield and an increase in apoptosis. U0126 dose-dependently protected HT29 cells from these antiproliferative effects of NS-398, indicating an antiproliferative role for sustained ERK-1/-2 activation in response to this NSAID. These results point to a key role for the MEK/ERK signalling pathway in mediating the effects of a COX-2-selective NSAID on colorectal carcinoma cells.
...
PMID:The MEK/ERK pathway mediates COX-2-selective NSAID-induced apoptosis and induced COX-2 protein expression in colorectal carcinoma cells. 1199 99

The CXC subfamily of chemokines plays an important role in diverse processes, including inflammation, wound healing, growth regulation, angiogenesis, and tumorigenesis. The CXC chemokine CXCL1, or MGSA/GROalpha, is traditionally considered to be responsible for attracting leukocytes into sites of inflammation. To better understand the molecular mechanisms by which CXCL1 induces CXCR2-mediated chemotaxis, the signal transduction components involved in CXCL1-induced chemotaxis were examined. It is shown here that CXCL1 induces cdc42 and PAK1 activation in CXCR2-expressing HEK293 cells. Activation of the cdc42-PAK1 cascade is required for CXCL1-induced chemotaxis but not for CXCL1-induced intracellular Ca2+ mobilization. Moreover, CXCL1 activation of PAK1 is independent of ERK1/2 activation, a conclusion based on the observations that the inhibition of MEK-ERK activation by expression of dominant negative ERK or by the MEK inhibitor, PD98059, has no effect on CXCL1-induced PAK1 activation or CXCL1-induced chemotaxis.
...
PMID:PAK1 kinase is required for CXCL1-induced chemotaxis. 1203 44

Activation of the mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-mitogen-activated protein kinase (MAPK) pathway is a frequent event in tumorigenesis, and analysis of human breast carcinomas demonstrates that 25-50% of these tumors express elevated levels of activated MAPK1/2. However, a direct role for MEK1 in regulating the invasive and metastatic potential of mammary epithelial cells remains to be established. To directly address the role of constitutive MEK1 signaling in transformation, we have selected the murine mammary epithelial cell line, EpH4, as a model system. EpH4 cells expressing constitutively activated MEK1 display invasive growth in 3-dimensional collagen gels and enhanced motility, and metastatic potential in modified Boyden chamber assays. Furthermore, analysis of markers of normal epithelial morphology by immunofluorescence revealed reorganization of the actin cytoskeleton, and mislocalization of beta-catenin and ZO-1 away from sites of cell-cell contact. However, in contrast to expectations, these changes occurred independently of an epithelial to mesenchymal transition, a change seen frequently in transformed epithelial cells. Moreover, transplantation of EpH4 cells expressing constitutively activated MEK1 into the cleared mammary fat pads of immune-competent hosts rapidly produced tumors that were highly invasive, well vascularized, and readily metastasized to distant organs. Gene expression profiling was performed to identify the downstream targets of MEK1 signaling. Constitutive MEK1 induced the expression of genes involved in proliferation and of matrix metalloproteinases, which regulate invasion and metastasis. These results demonstrate that constitutively activated MEK1 brings about robust tumorigenic changes in murine mammary epithelial cells, and mediates their invasiveness and metastasis in vivo without a requirement for epithelial to mesenchymal transition.
...
PMID:MEK1 signaling mediates transformation and metastasis of EpH4 mammary epithelial cells independent of an epithelial to mesenchymal transition. 1218 38

Protein kinase C (PKC), a family of serine-threonine kinases, has been implicated in the regulation of colon tumorigenesis. However, the specific isoform of PKC involved in this process is not clear. In the present study, we found that treatment of the cultured human colon cancer cell line COLO-205 with a PKC agonist, 12-O-tetradecanoylphorbol-13-acetate (TPA), resulted in cell-cycle arrest at the G(0)/G(1) phase, decrease in cell number, PKCgamma isoform translocation, and upregulation of p21(Cip1) protein. Pretreatment of the cells with a PKC inhibitor, staurosporine, prevented the TPA-induced upregulation of p21(Cip1) protein. Based on the findings of the present study including that (a) both extracellular signal-regulated kinase (ERK) and c-jun N-terminal kinase (JNK) were activated in the TPA-treated COLO-205 cells, (b) pretreatment with the mitogen-activated protein kinase kinase inhibitor PD98059 but not with the p38 mitogen-activated protein kinase inhibitor SB203580 blocked the TPA-induced p21(Cip1) in COLO-205 cells, and (c) transient transfection of the COLO-205 cells with dominant negative ERK or JNK plasmid significantly suppressed the TPA-induced p21(Cip1) protein induction, we conclude that both the ERK and JNK pathways are involved in the TPA-induced upregulation of p21(Cip1) protein in the COLO-205 cells.
...
PMID:Involvement of both extracellular signal-regulated kinase and c-jun N-terminal kinase pathways in the 12-O-tetradecanoylphorbol-13-acetate-induced upregulation of p21(Cip1) in colon cancer cells. 1220 64

The MEK family of protein kinases plays key roles in regulating cellular responses to mitogens as well as environmental stress. Inappropriate activation of these kinases contributes to tumorigenesis. In contrast, anthrax lethal factor, the principal virulence factor of anthrax toxin, has been demonstrated to selectively inactivate MEKs. In this article we will discuss recent advances in our understanding of molecular aspects of the pathogenesis of anthrax, emphasizing the potential role of MEK signalling in this disease, and outline novel strategies to use anthrax lethal toxin in the treatment of cancer.
...
PMID:Anthrax, MEK and cancer. 1242 3

The helix-loop-helix protein Id-1 has been suggested to play a positive role in cell proliferation and tumorigenesis of many types of human cancers. However, little is known about the molecular mechanism involved in the function of Id-1. In this study, using four stable Id-1 transfectant clones, we investigated the involvement of MAPK signaling pathway in the Id-1 induced serum independent prostate cancer cell growth. Our results demonstrated that both transient and stable ectopic Id-1 expression in prostate cancer LNCaP cells led to activation of the Raf/MEK1/2 signaling pathway. In addition, inhibition of MEK1/2 phosphorylation by one of its inhibitors, PD098059, resulted in the decreased cell cycle S phase fraction and cell growth rate, suggesting that activation of MAPK signaling pathway is essential for Id-1 induced prostate cancer cell proliferation. Furthermore, treatment with antisense oligonucleotide complementary to Id-1 mRNA in PC-3 and DU145 cells resulted in a decreased Id-1 expression which was accompanied by decreased Egr-1 protein. Our results suggest for the first time that the function of Id-1 is associated with MAPK signaling pathway activation and indicate a possible novel mechanism in which Id-1 regulates prostate cancer cell growth and tumorigenesis.
...
PMID:Activation of MAPK signaling pathway is essential for Id-1 induced serum independent prostate cancer cell growth. 1246 69

Malignant melanoma is the cancer with the most rapid increase in incidence in the United States. Ultraviolet light and deficiency of the p16ink4a gene are known factors that predispose one to the development of malignant melanoma. The signal transduction pathways that underlie the progression of melanoma from their precursors, atypical nevi, are not well understood. We examined activation of the MAP kinase pathway in atypical nevi and melanoma cells and found that this pathway is activated in melanomas. To determine the functional significance of this activation, we introduced constitutively active MAP kinase kinase (MAPKK) into immortalized melanocytes. The introduction of this gene into melanocytes leads to tumorigenesis in nude mice, activation of the angiogenic switch, and increased production of the proangiogenic factor, vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs). Activation of MAP kinase signaling may be an important pathway involved in melanoma transformation. Inhibition of MAP kinase signaling may be useful in the prevention and treatment of melanoma.
...
PMID:Malignant transformation of melanocytes to melanoma by constitutive activation of mitogen-activated protein kinase kinase (MAPKK) signaling. 1251 83

Dysregulated activation of Ras or its downstream effectors such as mitogen-activated protein kinase kinase and ERK has been shown to play a critical role in tumorigenesis of many cancer types. However, in melanoma, activating mutations in Ras are rarely observed and are limited to N-Ras in UV-exposed cells. In this study, we identify constitutively activated ERK in almost all melanoma cell lines and in tumor tissues tested, which is in contrast to normal melanocytes and several early stage radial growth phase melanoma lines where ERK can be activated by serum or growth factors. Constitutive activation of ERK is preceded by phosphorylation of mitogen-activated protein kinase kinase and c-RAF. In all of the melanoma cell lines tested, Ras is constitutively activated without underlying mutations. On the contrary, activating mutations in the kinase domain of BRAF are present in the majority of the cell lines tested. Furthermore, ERK activation can be partially inhibited from the cell surface using inhibitors of fibroblast growth factor and hepatocyte growth factor but not interleukin 8 signaling pathways. These data suggest that melanoma growth, invasion, and metastasis are attributable to constitutively activated ERK apparently mediated by excessive growth factors through autocrine mechanisms and BRAF kinase activation.
...
PMID:Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation. 1259 21

The AP-1 transcription factor plays an essential role in cell proliferation and tumorigenesis. It was previously shown that the fra-1 gene product is upregulated by various oncogenes and is involved in the in vitro and in vivo transformation of thyroid cells. Here we show that the ras oncogene-dependent accumulation of Fra-1 is mediated by a positive feedback mechanism which requires both transcriptional autoregulation and posttranslational stabilization of the protein. The oncogene-dependent transcriptional activation involves the cooperation between both Raf-dependent and Raf-independent pathways and is mediated by an AP-1 site within the fra-1 first intron, which becomes stably occupied by a transcriptionally active Fra-1-containing complex in ras-transformed cells. The posttranslational stabilization results in a drastic increase in the Fra-1 half-life in ras-transformed cells and is totally dependent on the activity of the MEK/ERK phosphorylation pathway. The analysis of the Fra-1 transactivation potential shows that the protein is able to stimulate a heterologous promoter in a ras-dependent manner, but the transactivating activity requires the recruitment of a heterodimeric partner. These data show that the alteration of multiple regulatory mechanisms is required for the constitutive activation of Fra-1 as a nuclear target of ras transformation.
...
PMID:Accumulation of Fra-1 in ras-transformed cells depends on both transcriptional autoregulation and MEK-dependent posttranslational stabilization. 1277 79

Many pro-apoptotic signals activate caspase-9, an initiator protease that activates caspase-3 and downstream caspases to initiate cellular destruction. However, survival signals can impinge on this pathway and suppress apoptosis. Activation of the Ras-Raf-MEK-ERK mitogen-activated protein kinase (MAPK) pathway is associated with protection of cells from apoptosis and inhibition of caspase-3 activation, although the targets are unknown. Here, we show that the ERK MAPK pathway inhibits caspase-9 activity by direct phosphorylation. In mammalian cell extracts, cytochrome c-induced activation of caspases-9 and -3 requires okadaic-acid-sensitive protein phosphatase activity. The opposing protein kinase activity is overcome by treatment with the broad-specificity kinase inhibitor staurosporine or with inhibitors of MEK1/2. Caspase-9 is phosphorylated at Thr 125, a conserved MAPK consensus site targeted by ERK2 in vitro, in a MEK-dependent manner in cells stimulated with epidermal growth factor (EGF) or 12-O-tetradecanoylphorbol-13-acetate (TPA). Phosphorylation at Thr 125 is sufficient to block caspase-9 processing and subsequent caspase-3 activation. We suggest that phosphorylation and inhibition of caspase-9 by ERK promotes cell survival during development and tissue homeostasis. This mechanism may also contribute to tumorigenesis when the ERK MAPK pathway is constitutively activated.
...
PMID:Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK. 1279 50


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---